Patent application title: Methods and compositions using immunomodulatory compounds for the treatment and management of central nervous system disorders or diseases

Abstract:

Methods of treating, preventing and/or managing central nervous system
disorders, such as Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's
Disease) and related syndromes are disclosed. Specific methods encompass
the administration of an immunomodulatory compound of the invention, or a
pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,
clathrate, or prodrug thereof, alone or in combination with a second
active ingredient. Pharmaceutical compositions, single unit dosage forms,
and kits suitable for use in methods of the invention are also disclosed.

Claims:

1-2. (canceled)

3. A method of treating amyotrophic lateral sclerosis, which comprises
administering to a patient having amyotrophic lateral sclerosis about 5
to about 50 mg per day of
N-{[2-(2,6-dioxo(3-piperidyl)-1,3-dioxoisoindolin-4-yl]methyl}cyclopropyl-
carboxamide having the formula:or a pharmaceutically acceptable salt,
solvate or stereoisomer thereof.

4-10. (canceled)

11. The method of claim 3, further comprising administering a
therapeutically effective amount of at least one second active
ingredient.

12-14. (canceled)

15. The method of claim 11, wherein the second active ingredient is
riluzole, a dopamine agonist, a monoamine oxidase inhibitor (MAO), a
catechol-O-methyltransferase inhibitor (COMT), amantadine, a
cholinesterase inhibitor, an antiemetic, an antioxidant or an
anti-inflammatory agent.

16. (canceled)

17. The method of claim 3, wherein the stereoisomer of the compound is the
R or S enantiomer.

18-21. (canceled)

22. The method of claim 3, wherein the compound is administered orally.

23. The method of claim 3, wherein the compound is administered in the
form of a tablet or capsule.

24. The method of claim 3, wherein the compound is administered in the
amount of about 5 mg to 25 mg per day.

25. The method of claim 3, wherein the compound is administered in the
amount of about 1 mg to 5 mg per day.

26. The method of claim 3, wherein the compound is administered in the
form of a capsule.

27. The method of claim 26, wherein the compound is administered in the
capsule of 5 mg, 10 mg, 15 mg or 25 mg.

Description:

[0001]This invention claims the benefit of U.S. Provisional Application
No. 60/533,862, filed Dec. 30, 2003, which is incorporated herein in its
entirety by reference.

1. FIELD OF THE INVENTION

[0002]This invention relates, in part, to methods of treating, preventing
and/or managing central nervous system disorders, including but not
limited to, Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease)
and related disorders which comprise the administration of one or more
immunomodulatory compounds or a pharmaceutically acceptable salt,
solvate, hydrate, stereoisomer, clathrate or prodrug thereof, alone or in
combination with known therapeutics.

2. BACKGROUND OF THE INVENTION

[0003]Central nervous system disorders affect a wide range of the
population with differing severity. Generally, the major feature of this
class of disorders include the significant impairment of cognition or
memory that represents a marked deterioration from a previous level of
functioning. Dementia, for example, is characterized by several cognitive
impairments including significant memory deficit and can stand alone or
be an underlying characteristic feature of a variety of diseases,
including Alzheimer Disease, Parkinson Disease, Huntington's Disease, and
Multiple Sclerosis to name but a few. Other central nervous system
disorders include delirium, or disturbances in consciousness that occur
over a short period of time, and amnestic disorder, or discreet memory
impairments that occur in the absence of other central nervous system
impairments.

[0004]2.1 IMIDS®

[0005]A number of studies have been conducted with the aim of providing
compounds that can safely and effectively be used to treat diseases
associated with abnormal production of TNF-α. See, e.g., Marriott,
J. B., et al., Expert Opin. Biol. Ther. 1(4):1-8 (2001); G. W. Muller, et
al., Journal of Medicinal Chemistry 39(17): 3238-3240 (1996); and G. W.
Muller, et al., Bioorganic & Medicinal Chemistry Letters 8: 2669-2674
(1998). Some studies have focused on a group of compounds selected for
their capacity to potently inhibit TNF-α production by LPS
stimulated PBMC. L. G. Corral, et al, Ann. Rheum. Dis. 58:(Suppl 1)
1107-1113 (1999). These compounds, which are referred to as IMiDS®
(Celgene Corporation) or Immunomodulatory Drugs, show not only potent
inhibition of TNF-α but also marked inhibition of LPS induced
monocyte IL1β and IL12 production. LPS induced IL6 is also inhibited
by immunomodulatory compounds, albeit partially. These compounds are
potent stimulators of LPS induced IL10. Id. Particular examples of
IMiD®s include, but are not limited to, the substituted
2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted
2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles described in U.S. Pat. Nos.
6,281,230 and 6,316,471, both to G. W. Muller, et al.

[0006]2.2 Amyotrophic Lateral Sclerosis

[0007]Amyotrophic Lateral Sclerosis (ALS), commonly known as Lou Gehrig's
Disease in the United States, is a neurodegenerative disorder that
affects the upper and lower motor neurons resulting in the wasting away
of muscles that have lost their innervation. Nature, 1993, 364(6435) 362.
As motor neurons degenerate, they can no longer send impulses to the
muscle fibers that normally result in muscle movement. ALS usually
develops in humans between the ages of 40 and 70. Early symptoms of ALS
often include increasing muscle weakness, especially involving the arms
and legs, speech, swallowing and breathing. Likewise, ALS can cause
slurred speech and difficulty breathing. Pathological characteristics
include anterior nerve root shrinkage in addition to spinal cord atrophy.
Brain Res. Bull., 1993, 30(3-4), 359-64.

[0008]There are three classifications of ALS: Sporadic ALS which
represents 90-95% of all ALS cases; Familial ALS which occurs more than
once in a family lineage and accounts for 5 to 10% of all cases; and
Guamanian ALS, representing an extremely high incidence of ALS observed
in Guam and the Trust Territories of the Pacific in the 1950's. ALS
typically causes total paralysis and respiratory failure within five
years of onset. 50% of ALS patients die within eighteen months after
diagnosis.

[0009]At present, riluzole (Rilutek®), a glutamate inhibitor, is the
only approved therapy for ALS, and no other therapies for ALS, and no
agents are consistently effective in preventing the progression of the
disease. The majority of therapeutics that are in current use focus on
the management of the symptoms of ALS. However, due to the side effects
and unattractive dosing requirements of these drugs, new methods and
compounds that are able to treat ALS and its symptoms are highly
desirable.

[0010]2.3 Parkinson Disease

[0011]Parkinson Disease (PD) is the second most common neurodegenerative
disease and affects approximately 1% of the population over 50 years of
age. Polymeropoulos et. al., 1996, Science 274: 1197-1198. Approximately
one million Americans suffer from PD, and each year 50,000 individuals
are diagnosed with the disorder. Olson, L., 2000, Science 290:721-724.
Because early symptoms of PD may go unrecognized, perhaps as many as 5 to
10% of individuals over 60 years of age may have the illness. Olson, L.,
2000, Science 290:721-724.

[0012]It has been known since the 1960s that loss of dopamine neurons in
the nigrostriatal pathway of the brain results in the motor abnormalities
characteristic of PD. Typical onset of PD occurs in mid to late adulthood
with progressive clinical features. Some of the physical manifestations
of PD include resting tremors, muscular rigidity, postural instability,
and dementia. Pathologic characteristics of PD include a loss of
dopaminergic neurons in the substantia nigra (SN) as well as the presence
of intracellular inclusions or Lewy Bodies in surviving neurons in
various areas of the brain. Nussbaum, R. L. and Polymeropoulos, M. H.,
1997, Hum. Molec. Genet. 6: 1687-1691. Interestingly, many other diseases
have parkisonian motor features. The motor symptoms in PD are generally
thought to result from the deficiency or dysfunction of dopamine or
dopaminergic neurons in the substantia nigra. Nussbaum, R. L.,
Polymeropoulos, M. H., 1997, Hum. Molec. Genet. 6: 1687-1691. Evidence
has also suggested that molecular chaperones, specifically heat shock
proteins, HSP70 and HSP40, may play a role in PD progression. Auluck et.
al., 2002, Science 295: 865-868.

[0013]Much controversy exists regarding the etiology of PD, and there is
evidence that both genetic and environmental factors may contribute to
the disease. A study of the nuclear families of 948 PD cases concluded
that a rare major mendelian inheritance gene, that influences age of
onset, exists. Maher et. al., 2002, Am. J. Med. Genet. 109: 191-197. This
study also suggested the existence of a gene that influences
susceptibility. Other evidence also suggests that environmental factors
may be more significant than genetic factors in contributing to PD. Calne
et. al., 1987, Canad. J. Neurol. Sci. 14: 303-305. Researchers have
concluded that most cases of PD are caused by environmental factors
superimposed on a background of slow and sustained neuronal loss due to
aging. Calne, D. B. and Langston, J. W., 1993, Lancet II: 1457-1459.
While the etiology remains unclear, it is likely that both genetic and
environmental factors contribute to PD, and that environmental factors
act upon genetic susceptibility to cause the disease. Recent evidence in
animal models of Parkinson disease, suggests that anti-inflammatory
agents inhibit dopaminergic cell death. McGeer et. al, 2001, B.C. Med. J.
43:138-141.

[0014]While a cure is not currently available for Parkinson Disease,
traditional treatment has focused on responding to the effect of dopamine
loss in the brain. Therapy using dopamine precursor, levodopa, became the
treatment of choice when it was discovered that the compound could
alleviate PD symptoms, thereby improving the quality of life for affected
individuals. Unfortunately, it has become clear that long-term levodopa
administration can have side affects. Caraceni et. al., 1994 Neurology,
41:380. A variety of therapeutic strategies have been developed for the
treatment of PD. MPTP, a neurotoxin known to specifically damage dopamine
neurons, is commonly used as a model for the effects of PD. In one study,
investigators used lentiviral vectors to deliver glial cell line derived
neurotrophic factor (GDNF) to the striatum and SN of rhesus monkeys that
had been treated one week prior with MPTP. Kordower et. al., 2000,
Science 290: 767-773. GDNF is known to have trophic effects upon
degenerating nigrostriatal neurons in nonhuman primate models of
Parkinson disease. Results of the study showed that GDNF augmented
dopaminergic function in aged monkeys and reversed functional deficits
and prevented nigrostriatal degeneration in monkeys that had been treated
with MPTP. It was also noted that GDNF treatment reversed motor deficits
in MPTP treated monkeys. This study also concluded that GDNF delivery
could prevent nigrostriatal degeneration and induce regeneration of
neurons in primate models of PD. Kordower et. al., 2000, Science 290:
767-773.

[0015]Another study, using electrical inhibition and pharmacologic
silencing of the subthalamic nucleus (STN), demonstrated that the
alteration of basal ganglia network activity could improve motor network
activity in PD, presumably by suppressing the firing activity of neurons
in the SN. Luo et. al., 2002, Science 298: 425-429. Investigators used an
adeno-associated virus to transduce excitatory glutaminergic neurons in
the rat STN with glutamic acid decarboxylase (GAD) to demonstrate that
the change provided neuroprotection to the dopaminergic cells from toxic
insults. Interestingly, rats with the transduced gene also showed
significant improvement from parkinsonian phenotypes.

[0016]2.4 Alzheimer Disease

[0017]Alzheimer disease (AD) is an increasingly prevalent form of
neurodegeneration that accounts for approximately 50%-60% of the overall
cases of dementia among people over 65 years of age. It currently affects
an estimated 15 million people worldwide and owing to the relative
increase of elderly people in the population its prevalence is likely to
increase over the next 2 to 3 decades. Alzheimer disease is a progressive
disorder with a mean duration of around 8.5 years between onset of
clinical symptoms and death. Death of pyramidal neurons and loss of
neuronal synapses in brains regions associated with higher mental
functions results in the typical symptoms, characterized by gross and
progressive impairment of cognitive function (Francis et al., 1999, J.
Neurol. Neurosurg. Psychiatry 66:137-47). Alzheimer disease is the most
common form of both senile and presenile dementia in the world and is
recognized clinically as relentlessly progressive dementia that presents
with increasing loss of memory, intellectual function and disturbances in
speech (Merritt, 1979, A Textbook of Neurology, 6th edition, pp. 484-489
Lea & Febiger, Philadelphia). The disease itself usually has a slow and
insidious progress that affects both sexes equally, worldwide. It begins
with mildly inappropriate behavior, uncritical statements, irritability,
a tendency towards grandiosity, euphoria and deteriorating performance at
work; it progresses through deterioration in operational judgment, loss
of insight, depression and loss of recent memory; it ends in severe
disorientation and confusion, apraxia of gait, generalized rigidity and
incontinence (Gilroy & Meyer, 1979, Medical Neurology, pp. 175-179
MacMillan Publishing Co.).

[0018]The etiology of Alzheimer disease is unknown. Evidence for a genetic
contribution comes from several important observations such as the
familial incidence, pedigree analysis, monozygotic and dizygotic twin
studies and the association of the disease with Down's syndrome (for
review see Baraitser, 1990, The Genetics of Neurological Disorders, 2nd
edition, pp. 85-88). Nevertheless, this evidence is far from definitive
and it is clear that one or more other factors are also required.
Elevated concentrations of aluminum have been found in the brains of some
patients dying with Alzheimer disease (Crapper et al., 1976, Brain,
99:67-80) and one case report has documented markedly elevated levels of
manganese in the tissues of a patient with Alzheimer disease (Banta &
Markesberg, 1977, Neurology, 27:213-216), which has led to the suggestion
that high levels of these metals may be neurotoxic and lead to the
development of Alzheimer disease. It was interesting that the aluminum
ions were found to be associated mainly with the nuclear chromatin in
brain regions most likely to display neurofibrillary tangles in Alzheimer
disease. However, from a statistical point of view the absolute
differences found for the aluminum levels between normal and Alzheimer
brains were far from convincing. It has recently been suggested that
defects in the transcriptional splicing of mRNA coding for the tau
complex of microtubule associated proteins occur (for review see Kosik,
1990, Curr. Opinion Cell Biol., 2:101-104) and/or that inappropriate
phosphorylation of these proteins exists (Grundke-Igbak et al., 1986,
Proc. Natl. Acad. Sci. USA, 83:4913-4917; Wolozin & Davies, 1987, Ann.
Neurol. 22:521-526; Hyman et al., 1988, Ann. Neurol., 23:371-379; Bancher
et al., 1989, Brain Res., 477:90-99). Furthermore, reduction in the
enzymes involved in the synthesis of acetylcholine has led to the view of
Alzheimer disease as a cholinergic system failure (Danes & Moloney, 1976,
Lancet, ii: 1403-14). However, even if cholinergic neurons are most at
risk in Alzheimer disease, it appears likely that these reductions in
enzyme activity are secondary to the degenerative process itself rather
than causally related.

[0019]At present, there are no proven therapies for Alzheimer disease, and
no agents are consistently effective in preventing the progression of the
disease. The majority of therapeutics that are in current use focus on
the management of the symptoms of AD. These strategies have employed the
use of anti-psychiatric drugs as well as neuroleptic agents and
acetylcholinesterase inhibitors. However, due to the side effects and
unattractive dosing requirements of these drugs, new methods and
compounds that are able to treat AD and its symptoms are highly
desirable.

3. SUMMARY OF THE INVENTION

[0020]This invention encompasses methods of treating or preventing central
nervous system disorders and related disorders which comprise
administering to a patient in need of such treatment or prevention a
therapeutically or prophylactically effective amount of an
immunomodulatory compound of the invention, or a pharmaceutically
acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug
thereof. Central nervous system disorders include, but are not limited
to, Amyotrophic Lateral Sclerosis, Alzheimer Disease, Parkinson Disease,
Huntington's Disease, Multiple Sclerosis other neuroimmunological
disorders such as Tourette Syndrome, delerium, or disturbances in
consciousness that occur over a short period of time, and amnestic
disorder, or discreet memory impairments that occur in the absence of
other central nervous system impairments. The invention also encompasses
methods of managing neurodegenerative central nervous system disorders
(e.g., lengthening the time of remission of their symptoms) which
comprise administering to a patient in need of such management a
prophylactically effective amount of an immunomodulatory compound of the
invention, or a pharmaceutically acceptable salt, solvate, hydrate,
stereoisomer, clathrate, or prodrug thereof. Each of these methods
includes specific dosing or dosing regimens including cycling therapy.

[0021]The invention further encompasses pharmaceutical compositions,
single unit dosage forms, and kits suitable for use in treating,
preventing and/or managing central nervous system disorders, preferably
ALS, which comprise an immunomodulatory compound of the invention, or a
pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,
clathrate, or prodrug thereof.

[0022]In particular embodiments of the invention, one or more IMiDs are
used, administered, or formulated with one or more second active
ingredients to treat, prevent or manage central nervous system disorders,
preferably ALS. Examples of the second active ingredients include but are
not limited to dopamine agonists, Levodopa, compounds used to augment
Levodopa therapy such as monoamine oxidase inhibitors (MAO) and
catechol-O-methyltransferase inhibitors (COMT), cholinesterase
inhibitors, glutamine inhibitors, amantadine, anticholinergics,
antiemetics, and other standard therapies for central nervous system
disorders. In another example, the second active ingredients are
anti-inflammatory agents, including, but not limited to, nonsteroidal
anti-inflammatory drugs (NSAIDs), PDE-4 inhibitors, Jun N terminal kinase
inhibitors, Methotrexate, Leflunomide, antimalarial drugs and
sulfasalazine, gold salts, glucocorticoids, immunosuppressive agents, and
other standard therapies for Parkinson Disease and related disorders.

[0024]Another embodiment of the invention encompasses methods of managing
a central nervous system disorder, which comprises administering to a
patient in need of such management a prophylactically effective amount of
an immunomodulatory compound of the invention, or a pharmaceutically
acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug
thereof.

[0025]Another embodiment of the invention encompasses a method of
treating, preventing and/or managing a central nervous system disorder,
which comprises administering to a patient in need of such treatment,
prevention and/or management a therapeutically or prophylactically
effective amount of an immunomodulatory compound of the invention, or a
pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,
clathrate, or prodrug thereof and a therapeutically or prophylactically
effective amount of a second active agent. Without being limited by
theory, it is believed that the combined use of such agents may reduce or
eliminate adverse effects associated with some immunomodulatory
compounds, thereby allowing the administration of larger amounts of
immunomodulatory compounds to patients and/or increasing patient
compliance. It is further believed that immunomodulatory compounds may
reduce or eliminate adverse effects associated with some conventional ALS
agents, thereby allowing the administration of larger amounts of the
agents to patients and/or increasing patient compliance.

[0026]Another embodiment of the invention encompasses a method of
reversing, reducing or avoiding an adverse effect associated with the
administration of conventional therapy for central nervous system
disorders to a patient suffering from central nervous system disorders or
a related disorder, which comprises administering to a patient in need of
such reversion, reduction or avoidance a therapeutically or
prophylactically effective amount of an immunomodulatory compound of the
invention, or a pharmaceutically acceptable salt, solvate, hydrate,
stereoisomer, clathrate, or prodrug thereof.

[0027]Yet another embodiment of the invention encompasses a pharmaceutical
composition comprising an immunomodulatory compound of the invention, or
a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,
clathrate, or prodrug thereof, and a pharmaceutically acceptable carrier,
diluent or excipient wherein the composition is adapted for parenteral,
oral or transdermal administration and the amount is sufficient to treat
or prevent a central nervous system disorder, preferably ALS or to
ameliorate the symptoms or progress of the disease.

[0028]Also encompassed by the invention are single unit dosage forms
comprising an immunomodulatory compound of the invention, or a
pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,
clathrate, or prodrug thereof.

[0029]Second active agents can be large molecules (e.g., proteins) or
small molecules (e.g., synthetic inorganic, organometallic, or organic
molecules). The examples of the second active agent include, but are not
limited to, cytokines, hematopoietic growth factors, anti-cancer agents
such as topoisomerase inhibitors, anti-angiogenic agents, microtubule
stabilizing agents, apoptosis inducing agents, alkylating agents and
other conventional chemotherapy described in the Physician's Desk
Reference 2002; cholinesterate inhibitors; antivirals; antifungals;
antibiotics; anti-inflammatories; immunomodulatory agents;
immunosuppressive agents such as cyclosporins; and other known or
conventional agents used in ALS, or Parkinson Disease patients. Specific
second active agents include but are not limited to riluzole for ALS, a
dopamine agonist or antagonist for Parkinson Disease or a cholinesterate
inhibitor for Alzheimer Disease.

[0030]The invention also encompasses kits which comprise an
immunomodulatory compound of the invention, or a pharmaceutically
acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug
thereof, a second active ingredient.

[0031]4.1 Immunomodulatory Compounds

[0032]Compounds of the invention can either be commercially purchased or
prepared according to the methods described in the patents or patent
publications disclosed herein. Further, optically pure compositions can
be asymmetrically synthesized or resolved using known resolving agents or
chiral columns as well as other standard synthetic organic chemistry
techniques. Compounds used in the invention may include immunomodulatory
compounds that are racemic, stereomerically enriched or stereomerically
pure, and pharmaceutically acceptable salts, solvates, stereoisomers, and
prodrugs thereof.

[0033]Preferred compounds used in the invention are small organic
molecules having a molecular weight less than about 1,000 g/mol, and are
not proteins, peptides, oligonucleotides, oligosaccharides or other
macromolecules.

[0035]TNF-α is an inflammatory cytokine produced by macrophages and
monocytes during acute inflammation. TNF-α is responsible for a
diverse range of signaling events within cells. Without being limited by
theory, one of the biological effects exerted by the immunomodulatory
compounds of the invention is the reduction of synthesis of TNF-α.
Immunomodulatory compounds of the invention enhance the degradation of
TNF-α mRNA.

[0036]Further, without being limited by theory, immunomodulatory compounds
used in the invention may also be potent co-stimulators of T cells and
increase cell proliferation dramatically in a dose dependent manner.
Immunomodulatory compounds of the invention may also have a greater
co-stimulatory effect on the CD8+ T cell subset than on the CD4+ T cell
subset. In addition, the compounds preferably have anti-inflammatory
properties, and efficiently co-stimulate T cells. Further, without being
limited by a particular theory, immunomodulatory compounds used in the
invention may be capable of acting both indirectly through cytokine
activation and directly on Natural Killer ("NK") cells, and increase the
NK cells' ability to produce beneficial cytokines such as, but not
limited to, IFN-γ.

[0037]Specific examples of immunomodulatory compounds, include, but are
not limited to, cyano and carboxy derivatives of substituted styrenes
such as those disclosed in U.S. Pat. No. 5,929,117;
1-oxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl) isoindolines and
1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidine-3-yl) isoindolines such as
those described in U.S. Pat. Nos. 5,874,448 and 5,955,476; the tetra
substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines described in
U.S. Pat. No. 5,798,368; 1-oxo and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)
isoindolines (e.g., 4-methyl derivatives of thalidomide), including, but
not limited to, those disclosed in U.S. Pat. Nos. 5,635,517, 6,476,052,
6,555,554, and 6,403,613; 1-oxo and 1,3-dioxoisoindolines substituted in
the 4- or 5-position of the indoline ring (e.g.,
4-(4-amino-1,3-dioxoisoindoline-2-yl)-4-carbamoylbutanoic acid) described
in U.S. Pat. No. 6,380,239; isoindoline-1-one and isoindoline-1,3-dione
substituted in the 2-position with 2,6-dioxo-3-hydroxypiperidin-5-yl
(e.g., 2-(2,6-dioxo-3-hydroxy-5-fluoropiperidin-5-yl)-4-aminoisoindolin-1-
-one) described in U.S. Pat. No. 6,458,810; a class of non-polypeptide
cyclic amides disclosed in U.S. Pat. Nos. 5,698,579 and 5,877,200;
aminothalidomide, as well as analogs, hydrolysis products, metabolites,
derivatives and precursors of aminothalidomide, and substituted
2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted
2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles such as those described in
U.S. Pat. Nos. 6,281,230 and 6,316,471; and isoindole-imide compounds
such as those described in U.S. patent application Ser. No. 09/972,487
filed on Oct. 5, 2001, U.S. patent application Ser. No. 10/032,286 filed
on Dec. 21, 2001, and International Application No. PCT/US01/50401
(International Publication No. WO 02/059106). The entireties of each of
the patents and patent applications identified herein are incorporated
herein by reference. Immunomodulatory compounds do not include
thalidomide.

[0038]Other specific immunomodulatory compounds of the invention include,
but are not limited to, 1-oxo- and 1,3 dioxo-2-(2,6-dioxopiperidin-3-yl)
isoindolines substituted with amino in the benzo ring as described in
U.S. Pat. No. 5,635,517 which is incorporated herein by reference. These
compounds have the structure I:

[0039]in which one of X and Y is C═O, the other of X and Y is C═O
or CH2, and R2 is hydrogen or lower alkyl, in particular
methyl. Specific immunomodulatory compounds include, but are not limited
to: [0040]1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline;
[0041]1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline;
[0042]1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline;
[0043]1-oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline;
[0044]1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; and
[0045]1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline.

[0046]Other specific immunomodulatory compounds of the invention belong to
a class of substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and
substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles, such as those
described in U.S. Pat. Nos. 6,281,230; 6,316,471; 6,335,349; and
6,476,052, and International Patent Application No. PCT/US97/13375
(International Publication No. WO 98/03502), each of which is
incorporated herein by reference. Representative compounds are of
formula:

[0047]in which: [0048]one of X and Y is C═O and the other of X and Y
is C═O or CH2; [0049](i) each of R1, R2, R3, and
R4, independently of the others, is halo, alkyl of 1 to 4 carbon
atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R1, R2,
R3, and R4 is --NHR5 and the remaining of R1,
R2, R3, and R4 are hydrogen; [0050]R5 is hydrogen or
alkyl of 1 to 8 carbon atoms; [0051]R6 is hydrogen, alkyl of 1 to 8
carbon atoms, benzyl, or halo; [0052]provided that R6 is other than
hydrogen if X and Y are C═O and (i) each of R1, R2,
R3, and R4 is fluoro or (ii) one of R1, R2, R3,
or R4 is amino.

[0053]Compounds representative of this class are of the formulas:

[0054]wherein R1 is hydrogen or methyl. In a separate embodiment, the
invention encompasses the use of enantiomerically pure forms (e.g.
optically pure (R) or (S) enantiomers) of these compounds.

[0055]Still other specific immunomodulatory compounds of the invention
belong to a class of isoindole-imides disclosed in U.S. Patent
Application Publication Nos. US 2003/0096841 and US 2003/0045552, and
International Application No. PCT/US01/50401 (International Publication
No. WO 02/059106), each of which are incorporated herein by reference.
Representative compounds are of formula II:

[0063]each occurrence of R6 is independently H,
(C1-C8)alkyl, (C2-C8)alkenyl,
(C2-C8)alkynyl, benzyl, aryl, (C2-C5)heteroaryl, or
(C0-C8)alkyl-C(O)O--R5 or the R6 groups can join to
form a heterocycloalkyl group;

[0068]R3 is (C1-C8)alkyl, (C3-C7)cycloalkyl,
(C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl,
(C0-C4)alkyl-C1-C6)heterocycloalkyl,
(C0-C4)alkyl-C2-C5)heteroaryl,
(C5-C8)alkyl-N(R6)2;
(C0-C8)alkyl-NH--C(O)O--R5;
(C1-C8)alkyl-OR5, (C1-C8)alkyl-C(O)OR5,
(C1-C8)alkyl-O(CO)R5, or C(O)OR5; and the other
variables have the same definitions.

[0069]In other specific compounds of formula II, R2 is H or
(C1-C4)alkyl.

[0070]In other specific compounds of formula II, R1 is
(C1-C8)alkyl or benzyl.

[0073]wherein Q is O or S, and each occurrence of R7 is independently
H, (C1-C8)alkyl, (C3-C7)cycloalkyl,
(C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl,
halogen, (C0-C4)alkyl-(C1-C6)heterocycloalkyl,
(C0-C4)alkyl-(C2-C5)heteroaryl,
(C0-C8)alkyl-N(R6)2, (C1-C8)alkyl-OR5,
(C1-C8)alkyl-C(O)OR5, (C1-C9)alkyl-O(CO)R5,
or C(O)OR5, or adjacent occurrences of R7 can be taken together
to form a bicyclic alkyl or aryl ring.

[0080]Still other specific immunomodulatory compounds of the invention
belong to a class of isoindole-imides disclosed in U.S. Patent
Application Publication Nos. US 2002/0045643, International Publication
No. WO 98/54170, and U.S. Pat. No. 6,395,754, each of which is
incorporated herein by reference. Representative compounds are of formula
III:

[0084](i) each of R1, R2, R3, or R4, independently of
the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4
carbon atoms or (ii) one of R1, R2, R3, or R4 is
nitro or --NHR5 and the remaining of R1, R2, R3, or
R4 are hydrogen;

[0088]R7 is m-phenylene or p-phenylene or --(CnH2n)-- in
which n has a value of 0 to 4;

[0089]each of R8 and R9 taken independently of the other is
hydrogen or alkyl of 1 to 8 carbon atoms, or R8 and R9 taken
together are tetramethylene, pentamethylene, hexamethylene, or
--CH2CH2X1CH2CH2-- in which X1 is --O--,
--S--, or --NH--;

[0090]R10 is hydrogen, alkyl of to 8 carbon atoms, or phenyl; and

[0091]* represents a chiral-carbon center.

[0092]Other representative compounds are of formula:

[0093]wherein:

[0094]one of X and Y is C═O and the other of X and Y is C═O or
CH2;

[0095](i) each of R1, R2, R3, or R4, independently of
the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4
carbon atoms or (ii) one of R1, R2, R3, and R4 is
--NHR5 and the remaining of R1, R2, R3, and R4
are hydrogen;

[0098]R7 is m-phenylene or p-phenylene or --(CnH2n)-- in
which n has a value of 0 to 4;

[0099]each of R8 and R9 taken independently of the other is
hydrogen or alkyl of 1 to 8 carbon atoms, or R8 and R9 taken
together are tetramethylene, pentamethylene, hexamethylene, or
--CH2CH2X1CH2CH2-- in which X1 is --O--,
--S--, or --NH--;

[0100]R10 is hydrogen, alkyl of to 8 carbon atoms, or phenyl.

[0101]Other representative compounds are of formula:

[0102]in which

[0103]one of X and Y is C═O and the other of X and Y is C═O or
CH2;

[0104]each of R1, R2, R3, and R4, independently of the
others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon
atoms or (ii) one of R1, R2, R3, and R4 is nitro or
protected amino and the remaining of R1, R2, R3, and
R4 are hydrogen; and

[0109](i) each of R1, R2, R3, and R4, independently of
the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4
carbon atoms or (ii) one of R1, R2, R3, and R4 is
--NHR5 and the remaining of R1, R2, R3, and R4
are hydrogen;

[0110]R5 is hydrogen, alkyl of 1 to 8 carbon atoms, or
CO--R7--CH(R10NR8R9 in which each of R7,
R8, R9, and R10 is as herein defined; and

[0116]R7 is m-phenylene, p-phenylene or --(CnH2n)-- in
which n has a value of 0 to 4;

[0117]each of R8 and R9 taken independently of the other is
hydrogen or alkyl of 1 to 8 carbon atoms, or R8 and R9 taken
together are tetramethylene, pentamethylene, hexamethylene, or
--CH2CH2X1CH2CH2-- in which X1 is --O--,
--S-- or --NH--; and

[0118]R10 is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl.

[0119]Preferred immunomodulatory compounds of the invention are
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione and
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. The
compounds can be obtained via standard, synthetic methods (see e.g., U.S.
Pat. No. 5,635,517, incorporated herein by reference). The compounds are
available from Celgene Corporation, Warren, N.J.
4-(Amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione has the
following chemical structure:

[0120]The compound
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione has the
following chemical structure:

[0121]In another embodiment, specific immunomodulatory compounds of the
invention encompass polymorphic forms of 3-(4-amino-1-oxo-1,3
dihydro-isoindol-2-yl)-piperidene-2,6-dione such as Form A, B, C, D, E,
F, G and H, disclosed in U.S. provisional application No. 60/499,723
filed on Sep. 4, 2003, and the corresponding U.S. non-provisional
application Ser. No. 10/934,863, filed Sep. 3, 2004, both of which are
incorporated herein by reference. For example, Form A of
3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidene-2,6-dione is an
unsolvated, crystalline material that can be obtained from non-aqueous
solvent systems. Form A has an X-ray powder diffraction pattern
comprising significant peaks at approximately 8, 14.5, 16, 17.5, 20.5, 24
and 26 degrees 2θ, and has a differential scanning calorimetry
melting temperature maximum of about 270° C. Form A is weakly or
not hygroscopic and appears to be the most thermodynamically stable
anhydrous polymorph of 3-(4-amino-1-oxo-1,3
dihydro-isoindol-2-yl)-piperidine-2,6-dione discovered thus far.

[0122]Form B of 3-(4-amino-1-oxo-1,3
dihydro-isoindol-2-yl)-piperidene-2,6-dione is a hemihydrated,
crystalline material that can be obtained from various solvent systems,
including, but not limited to, hexane, toluene, and water. Form B has an
X-ray powder diffraction pattern comprising significant peaks at
approximately 16, 18, 22 and 27 degrees 2θ, and has endotherms from
DSC curve of about 146 and 268° C., which are identified
dehydration and melting by hot stage microscopy experiments.
Interconversion studies show that Form B converts to Form E in aqueous
solvent systems, and converts to other forms in acetone and other
anhydrous systems.

[0123]Form C of 3-(4-amino-1-oxo-1,3
dihydro-isoindol-2-yl)-piperidene-2,6-dione is a hemisolvated crystalline
material that can be obtained from solvents such as, but not limited to,
acetone. Form C has an X-ray powder diffraction pattern comprising
significant peaks at approximately 15.5 and 25 degrees 2θ, and has
a differential scanning calorimetry melting temperature maximum of about
269° C. Form C is not hygroscopic below about 85% RH, but can
convert to Form B at higher relative humidities.

[0124]Form D of 3-(4-amino-1-oxo-1,3
dihydro-isoindol-2-yl)-piperidene-2,6-dione is a crystalline, solvated
polymorph prepared from a mixture of acetonitrile and water. Form D has
an X-ray powder diffraction pattern comprising significant peaks at
approximately 27 and 28 degrees 2θ, and has a differential scanning
calorimetry melting temperature maximum of about 270° C. Form D is
either weakly or not hygroscopic, but will typically convert to Form B
when stressed at higher relative humidities.

[0125]Form E of 3-(4-amino-1-oxo-1,3
dihydro-isoindol-2-yl)-piperidene-2,6-dione is a dihydrated, crystalline
material that can be obtained by slurrying
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidene-2,6-dione in water
and by a slow evaporation of 3-(4-amino-1-oxo-1,3
dihydro-isoindol-2-yl)-piperidene-2,6-dione in a solvent system with a
ratio of about 9:1 acetone:water. Form E has an X-ray powder diffraction
pattern comprising significant peaks at approximately 20, 24.5 and 29
degrees 2θ, and has a differential scanning calorimetry melting
temperature maximum of about 269° C. Form E can convert to Form C
in an acetone solvent system and to Form G in a THF solvent system. In
aqueous solvent systems, Form E appears to be the most stable form.
Desolvation experiments performed on Form E show that upon heating at
about 125° C. for about five minutes, Form E can convert to Form
B. Upon heating at 175° C. for about five minutes, Form B can
convert to Form F.

[0126]Form F of 3-(4-amino-1-oxo-1,3
dihydro-isoindol-2-yl)-piperidene-2,6-dione is an unsolvated, crystalline
material that can be obtained from the dehydration of Form E. Form F has
an X-ray powder diffraction pattern comprising significant peaks at
approximately 19, 19.5 and 25 degrees 2θ, and has a differential
scanning calorimetry melting temperature maximum of about 269° C.

[0127]Form G of 3-(4-amino-1-oxo-1,3
dihydro-isoindol-2-yl)-piperidene-2,6-dione is an unsolvated, crystalline
material that can be obtained from slurrying forms B and E in a solvent
such as, but not limited to, tetrahydrofuran (THF). Form G has an X-ray
powder diffraction pattern comprising significant peaks at approximately
21, 23 and 24.5 degrees 2θ, and has a differential scanning
calorimetry melting temperature maximum of about 267° C.

[0128]Form H of 3-(4-amino-1-oxo-1,3
dihydro-isoindol-2-yl)-piperidene-2,6-dione is a partially hydrated
(about 0.25 moles) crystalline material that can be obtained by exposing
Form E to 0% relative humidity. Form H has an X-ray powder diffraction
pattern comprising significant peaks at approximately 15, 26 and 31
degrees 2θ, and has a differential scanning calorimetry melting
temperature maximum of about 269° C.

[0129]Other specific immunomodulatory compounds of the invention include,
but are not limited to, 1-oxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl)
isoindolines and 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidine-3-yl)
isoindolines such as those described in U.S. Pat. Nos. 5,874,448 and
5,955,476, each of which is incorporated herein by reference.
Representative compounds are of formula:

[0130]wherein Y is oxygen or H2 and

[0131]each of R1, R2, R3, and R4, independently of the
others, is hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4
carbon atoms, or amino.

[0132]Other specific immunomodulatory compounds of the invention include,
but are not limited to, the tetra substituted
2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines described in U.S. Pat. No.
5,798,368, which is incorporated herein by reference. Representative
compounds are of formula:

[0133]wherein each of R1, R2, R3, and R4,
independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or
alkoxy of 1 to 4 carbon atoms.

[0134]Other specific immunomodulatory compounds of the invention include,
but are not limited to, 1-oxo and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)
isoindolines disclosed in U.S. Pat. No. 6,403,613, which is incorporated
herein by reference. Representative compounds are of formula:

[0135]in which

[0136]Y is oxygen or H2,

[0137]a first of R1 and R2 is halo, alkyl, alkoxy, alkylamino,
dialkylamino, cyano, or carbamoyl, the second of R1 and R2,
independently of the first, is hydrogen, halo, alkyl, alkoxy, alkylamino,
dialkylamino, cyano, or carbamoyl, and

[0138]R3 is hydrogen, alkyl, or benzyl.

[0139]Specific examples of the compounds are of formula:

[0140]wherein a first of R1 and R2 is halo, alkyl of from 1 to 4
carbon atoms, alkoxy of from 1 to 4 carbon atoms, dialkylamino in which
each alkyl is of from 1 to 4 carbon atoms, cyano, or carbamoyl,

[0141]the second of R1 and R2, independently of the first, is
hydrogen, halo, alkyl of from 1 to 4 carbon atoms, alkoxy of from, 1 to 4
carbon atoms, alkylamino in which alkyl is of from 1 to 4 carbon atoms,
dialkylamino in which each alkyl is of from 1 to 4 carbon atoms, cyano,
or carbamoyl, and

[0142]R3 is hydrogen, alkyl of from 1 to 4 carbon atoms, or benzyl.
Specific examples include, but are not limited to,
1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-methylisoindoline.

[0143]Other representative compounds are of formula:

[0144]wherein a first of R1 and R2 is halo, alkyl of from 1 to 4
carbon atoms, alkoxy of from 1 to 4 carbon atoms, dialkylamino in which
each alkyl is of from 1 to 4 carbon atoms, cyano, or carbamoyl,

[0145]the second of R1 and R2, independently of the first, is
hydrogen, halo, alkyl of from 1 to 4 carbon atoms, alkoxy of from 1 to 4
carbon atoms, alkylamino in which alkyl is of from 1 to 4 carbon atoms,
dialkylamino in which each alkyl is of from 1 to 4 carbon atoms, cyano,
or carbamoyl, and

[0146]R3 is hydrogen, alkyl of from 1 to 4 carbon atoms, or benzyl.

[0147]Specific examples include, but are not limited to,
1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-methylisoindoline.

[0148]Other specific immunomodulatory compounds of the invention include,
but are not limited to, 1-oxo and 1,3-dioxoisoindolines substituted in
the 4- or 5-position of the indoline ring described in U.S. Pat. No.
6,380,239 and co-pending U.S. application Ser. No. 10/900,270, filed Jul.
28, 2004, which are incorporated herein by reference. Representative
compounds are of formula:

[0149]in which the carbon atom designated C* constitutes a center of
chirality (when n is not zero and R1 is not the same as R2);
one of X1 and X2 is amino, nitro, alkyl of one to six carbons,
or NH-Z, and the other of X1 or X2 is hydrogen; each of R1
and R2 independent of the other, is hydroxy or NH-Z; R3 is
hydrogen, alkyl of one to six carbons, halo, or haloalkyl; Z is hydrogen,
aryl, alkyl of one to six carbons, formyl, or acyl of one to six carbons;
and n has a value of 0, 1, or 2; provided that if X1 is amino, and n
is 1 or 2, then R1 and R2 are not both hydroxy; and the salts
thereof.

[0150]Further representative compounds are of formula:

[0151]in which the carbon atom designated C* constitutes a center of
chirality when n is not zero and R1 is not R2; one of X1
and X2 is amino, nitro, alkyl of one to six carbons, or NH-Z, and
the other of X1 or X2 is hydrogen; each of R1 and R2
independent of the other, is hydroxy or NH-Z; R3 is alkyl of one to
six carbons, halo, or hydrogen; Z is hydrogen, aryl or an alkyl or acyl
of one to six carbons; and n has a value of 0, 1, or 2.

[0152]Specific examples include, but are not limited to,
2-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-4-carbamoyl-butyric acid and
4-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-4-carbamoyl-butyric acid,
which have the following structures, respectively, and pharmaceutically
acceptable salts, solvates, prodrugs, and stereoisomers thereof:

[0153]Other representative compounds are of formula:

[0154]in which the carbon atom designated C* constitutes a center of
chirality when n is not zero and R1 is not R2; one of X1
and X2 is amino, nitro, alkyl of one to six carbons, or NH-Z, and
the other of X1 or X2 is hydrogen; each of R1 and R2
independent of the other, is hydroxy or NH-Z; R3 is alkyl of one to
six carbons, halo, or hydrogen; Z is hydrogen, aryl, or an alkyl or acyl
of one to six carbons; and n has a value of 0, 1, or 2; and the salts
thereof.

[0157]wherein one of X1 and X2 is nitro, or NH-Z, and the other
of X1 or X2 is hydrogen;

[0158]each of R1 and R2, independent of the other, is hydroxy or
NH-Z;

[0159]R3 is alkyl of one to six carbons, halo, or hydrogen;

[0160]Z is hydrogen, phenyl, an acyl of one to six carbons, or an alkyl of
one to six carbons; and

[0161]n has a value of 0, 1, or 2;

[0162]provided that if one of X1 and X2 is nitro, and n is 1 or
2, then R1 and R2 are other than hydroxy; and

[0163]if --COR2 and --(CH2)nCOR1 are different, the
carbon atom designated C constitutes a center of chirality. Other
representative compounds are of formula:

[0164]wherein one of X1 and X2 is alkyl of one to six carbons;

[0165]each of R1 and R2, independent of the other, is hydroxy or
NH-Z;

[0166]R3 is alkyl of one to six carbons, halo, or hydrogen;

[0167]Z is hydrogen, phenyl, an acyl of one to six carbons, or an alkyl of
one to six carbons; and

[0168]n has a value of 0, 1, or 2; and

[0169]if --COR2 and --(CH2)nCOR1 are different, the
carbon atom designated C* constitutes a center of chirality.

[0170]Still other specific immunomodulatory compounds of the invention
include, but are not limited to, isoindoline-1-one and
isoindoline-1,3-dione substituted in the 2-position with
2,6-dioxo-3-hydroxypiperidin-5-yl described in U.S. Pat. No. 6,458,810,
which is incorporated herein by reference. Representative compounds are
of formula:

[0171]wherein:

[0172]the carbon atoms designated * constitute centers of chirality;

[0173]X is --C(O)-- or --CH2--;

[0174]R1 is alkyl of 1 to 8 carbon atoms or --NHR3;

[0175]R2 is hydrogen, alkyl of 1 to 8 carbon atoms, or halogen;

[0176]and

[0177]R3 is hydrogen,

[0178]alkyl of 1 to 8 carbon atoms, unsubstituted or substituted with
alkoxy of 1 to 8 carbon atoms, halo, amino, or alkylamino of 1 to 4
carbon atoms,

[0179]cycloalkyl of 3 to 18 carbon atoms,

[0180]phenyl, unsubstituted or substituted with alkyl of 1 to 8 carbon
atoms, alkoxy of 1 to 8 carbon atoms, halo, amino, or alkylamino of 1 to
4 carbon atoms,

[0181]benzyl, unsubstituted or substituted with alkyl of 1 to 8 carbon
atoms, alkoxy of 1 to 8 carbon atoms, halo, amino, or alkylamino of 1 to
4 carbon atoms, or --COR4 in which

[0182]R4 is hydrogen,

[0183]alkyl of 1 to 8 carbon atoms, unsubstituted or substituted with
alkoxy of 1 to 8 carbon atoms, halo, amino, or alkylamino of 1 to 4
carbon atoms,

[0184]cycloalkyl of 3 to 18 carbon atoms,

[0185]phenyl, unsubstituted or substituted with alkyl of 1 to 8 carbon
atoms, alkoxy of 1 to 8 carbon atoms, halo, amino, or alkylamino of 1 to
4 carbon atoms, or

[0186]benzyl, unsubstituted or substituted with alkyl of 1 to 8 carbon
atoms, alkoxy of 1 to 8 carbon atoms, halo, amino, or alkylamino of 1 to
4 carbon atoms.

[0187]Compounds of the invention can either be commercially purchased or
prepared according to the methods described in the patents or patent
publications disclosed herein. Further, optically pure compounds can be
asymmetrically synthesized or resolved using known resolving agents or
chiral columns as well as other standard synthetic organic chemistry
techniques.

[0189]Compounds that are acidic in nature are capable of forming salts
with various pharmaceutically acceptable bases. The bases that can be
used to prepare pharmaceutically acceptable base addition salts of such
acidic compounds are those that form non-toxic base addition salts, i.e.,
salts containing pharmacologically acceptable cations such as, but not
limited to, alkali metal or alkaline earth metal salts and the calcium,
magnesium, sodium or potassium salts in particular. Suitable organic
bases include, but are not limited to, N,N-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine
(N-methylglucamine), lysine, and procaine.

[0190]As used herein, and unless otherwise specified, the term "solvate"
means a compound of the present invention or a salt thereof, that further
includes a stoichiometric or non-stoichiometric amount of solvent bound
by non-covalent intermolecular forces. Where the solvent is water, the
solvate is a hydrate.

[0191]As used herein and unless otherwise indicated, the term "prodrug"
means a derivative of a compound that can hydrolyze, oxidize, or
otherwise react under biological conditions (in vitro or in vivo) to
provide the compound. Examples of prodrugs include, but are not limited
to, derivatives of immunomodulatory compounds of the invention that
comprise biohydrolyzable moieties such as biohydrolyzable amides,
biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable
carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate
analogues. Other examples of prodrugs include derivatives of
immunomodulatory compounds of the invention that comprise --NO,
--NO2, --ONO, or --ONO2 moieties. Prodrugs can typically be
prepared using well-known methods, such as those described in 1 Burger's
Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E.
Wolff ed., 5th ed. 1995), and Design of Prodrugs (H. Bundgaard ed.,
Elsevier, N.Y. 1985).

[0193]As used herein, and unless otherwise specified, the term
"stereoisomer" encompasses all enantiomerically/stereomerically pure and
enantiomerically/stereomerically enriched compounds of this invention.

[0194]As used herein, and unless otherwise indicated, the term
"stereomerically pure" or "enantiomerically pure" means that a compound
comprises one stereoisomer and is substantially free of its counter
stereoisomer or enantiomer. For example, a compound is stereomerically or
enantiomerically pure when the compound contains 80%, 90%, or 95% or more
of one stereoisomer and 20%, 10%, or 5% or less of the counter
stereoisomer. In certain cases, a compound of the invention is considered
optically active or stereomerically/enantiomerically pure (i.e.,
substantially the R-form or substantially the S-form) with respect to a
chiral center when the compound is about 80% ee (enantiomeric excess) or
greater, preferably, equal to or greater than 90% ee with respect to a
particular chiral center, and more preferably 95% ee with respect to a
particular chiral center.

[0195]As used herein, and unless otherwise indicated, the term
"stereomerically enriched" or "enantiomerically enriched" encompasses
racemic mixtures as well as other mixtures of stereoisomers of compounds
of this invention (e.g., R/S=30/70, 35/65, 40/60, 45/55, 55/45, 60/40,
65/35 and 70/30). Various immunomodulatory compounds of the invention
contain one or more chiral centers, and can exist as racemic mixtures of
enantiomers or mixtures of diastereomers. This invention encompasses the
use of stereomerically pure forms of such compounds, as well as the use
of mixtures of those forms. For example, mixtures comprising equal or
unequal amounts of the enantiomers of a particular immunomodulatory
compounds of the invention may be used in methods and compositions of the
invention. These isomers may be asymmetrically synthesized or resolved
using standard techniques such as chiral columns or chiral resolving
agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and
Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al.,
Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon
Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving
Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre
Dame Press, Notre Dame, Ind., 1972).

[0196]It should be noted that if there is a discrepancy between a depicted
structure and a name given that structure, the depicted structure is to
be accorded more weight. In addition, if the stereochemistry of a
structure or a portion of a structure is not indicated with, for example,
bold or dashed lines, the structure or portion of the structure is to be
interpreted as encompassing all stereoisomers of it.

[0197]4.2 Second Active Ingredients

[0198]As discussed above, a second active ingredient or agent can be used
in the methods and compositions of the invention together with an
immunomodulatory compound, particularly conventional agents or therapies
used to treat or manage central nervous system disorders. Specific second
active agents also stimulate the division and differentiation of
committed erythroid progenitors in cells in vitro or in vivo.

[0199]In one embodiment, a second active ingredient can be administered
with an immunomodulatory compound. In a specific embodiment, the second
active ingredient is riluzole. In one embodiment, the second active
ingredient is a dopamine agonist or antagonist, for example, but not
limited to, Levodopa, L-DOPA, cocaine, α-methyl-tyrosine,
reserpine, tetrabenazine, benzotropine, pargyline, fenodolpam mesylate,
cabergoline, pramipexole dihydrochloride, ropinorole, amantadine
hydrochloride, selegiline hydrochloride, carbidopa, pergolide mesylate,
Sinemet CR, or Symmetrel.

[0200]In another embodiment, the second active ingredient that is
administered with an immunomodulatory compound is a MAO inhibitor, for
example, but not limited to, iproniazid, clorgyline, phenelzine and
isocarboxazid.

[0201]In another embodiment, the second active ingredient that is
administered with an immunomodulatory compound is a COMT inhibitor, for
example, but not limited to, tolcapone and entacapone.

[0206]Methods of this invention encompass methods of preventing, treating
and/or managing central nervous system disorders, preferably ALS,
Parkinson Disease, neuroimmunological disorders such as Tourette Syndrome
or Alzheimer Disease. As used herein, unless otherwise specified, the
term "preventing" includes but is not limited to, inhibition or the
averting of symptoms associated with neurodegenerative central nervous
system disorders. Central nervous system disorders, include, but are not
limited to, Amyotrophic Lateral Sclerosis (ALS); progressive motor
deterioration CNS trauma; hypokinetic disorders; bradykinesia; slowness
of movement; paucity of movement; impairment of dexterity; hypophonia;
monotonic speech; muscular rigidity; masked faces; decreased blinking;
stooped posture; decreased arm swinging when walking; micrographia;
parkinsonian tremor; parkinsonian gait; postural instability; festinating
gait; motion freezing; disturbances of cognition, mood, sensation, sleep
or autonomic function; dementia; depression and sleep disorders. As used
herein, unless otherwise specified, the term "treating" refers to the
administration of a composition after the onset of symptoms of central
nervous system disorders, preferably Parkinson Disease or a related
disorder whereas "preventing" refers to the administration prior to the
onset of symptoms, particularly to patients at risk of central nervous
system disorders, preferably Parkinson Disease or a related disorder. As
used herein and unless otherwise indicated, the term "managing"
encompasses preventing the recurrence of symptoms of central nervous
system disorders in a patient who had suffered from a central nervous
system disorder, lengthening the time the symptoms remain in remission in
a patient who had suffered from central nervous system disorders, and/or
preventing the occurrence of central nervous system disorders in patients
at risk of suffering from central nervous system disorders.

[0208]The invention encompasses methods of treating or preventing central
nervous system disorders, preferably ALS, Parkinson Disease or
Alzheimer's disease. In one embodiment, the methods of the invention are
used to treat or prevent disorders related to movement, including, but
not limited to, progressive motor deterioration, slow execution or
bradykinesia, paucity of movement or akinesia, movement disorders that
impair fine motor control and finger dexterity, and other manifestations
of bradykinesia, such as, but not limited to, hypophonia and monotonic
speech. In another embodiment, the methods of the invention are used to
treat or prevent disorders related to muscular rigidity, including, but
not limited to, a uniform increase in resistance to passive movement,
interruptions to passive movement, and combinations of rigidity and
dystonia. In a specific embodiment, methods of the invention are used to
treat inflammation associated with Parkinson or related disease. In yet
another embodiment of the invention, disorders resembling Parkinsonian
tremor are treated or prevented by the methods of the invention,
including but not limited to, tremors of the face, jaw, tongue, posture,
and other tremors that are present at rest and that attenuate during
movement. In another embodiment, the methods of the invention are used to
treat or prevent disorders in gait, including, but not limited to, those
resembling parkinsonian gait, shuffling, short steps, a tendency to turn
en bloc, and festinating gait. In another embodiment of the invention,
nonmotor symptoms are treated or prevented using the methods of the
invention, including, but not limited to, disorders of mood, cognition,
sensation, sleep, dementia, and depression. In other embodiment of the
invention secondary forms of parkinsonism are treated or prevented by the
methods of the invention, including, but not limited to, drug induced
parkinsonism, vascular parkinsonism, multiple system atrophy, progressive
supranuclear palsy, disorders with primary tau pathology, cortical basal
ganglia degeneration, parkinsonism with dementia, hyperkinetic disorders,
chorea, Huntington's disease, dystonia, Wilson disease, Tourette
syndrome, essential tremor, myoclonus, and tardive movement disorders. In
other embodiment of the invention other central nervous system disorders
are treated or prevented by the methods of the invention, including, but
not limited to Alzheimer Disease, Amyotrophic Lateral Sclerosis (ALS) and
CNS trauma.

[0209]Methods encompassed by this invention comprise administering an
immunomodulatory compound of the invention, or a pharmaceutically
acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug
thereof to a patient (e.g., a human) suffering, or likely to suffer, from
central nervous system disorders.

[0210]Another method comprises administering 1) an immunomodulatory
compound of the invention, or a pharmaceutically acceptable salt,
solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and 2) a
second active agent or active ingredient. Examples of examples of the
second active agents are also disclosed herein (see, e.g., section 4.2).

[0211]Administration of immunomodulatory compound and the second active
agents to a patient can occur simultaneously or sequentially by the same
or different routes of administration. The suitability of a particular
route of administration employed for a particular active agent will
depend on the active agent itself (e.g., whether it can be administered
orally without decomposing prior to entering the blood stream) and the
disease being treated. A preferred route of administration for thaliomide
is orally. Preferred routes of administration for the second active
agents or ingredients of the invention are known to those of ordinary
skill in the art. See, e.g., Physicians' Desk Reference, 1755-1760
(56th ed., 2002).

[0212]In one embodiment of the invention, the recommended daily dose range
of an immunomodulatory compound for the conditions described herein lie
within the range of from about 1 mg to about 10,000 mg per day, given as
a single once-a-day dose, or preferably in divided doses throughout a
day. More specifically, the daily dose is administered twice daily in
equally divided doses. Specifically, a daily dose range should be from
about 1 mg to about 5,000 mg per day, more specifically, between about 10
mg and about 2,500 mg per day, between about 100 mg and about 800 mg per
day, between about 100 mg and about 1,200 mg per day, or between about 25
mg and about 2,500 mg per day. In managing the patient, the therapy
should be initiated at a lower dose, perhaps about 1 mg to about 2,500
mg, and increased if necessary up to about 200 mg to about 5,000 mg per
day as either a single dose or divided doses, depending on the patient's
global response. In a particular embodiment, an immunomodulatory compound
can be preferably administered in an amount of about 400, 800, 1,200,
2,500, 5,000 or 10,000 mg a day as two divided doses.

[0213]In another embodiment, an immunomodulatory compound is administered
in conjunction with the second active agent. The second active agent is
administered orally, intravenously or subcutaneously and once or twice
daily in an amount of from about 1 to about 1000 mg, from about 5 to
about 500 mg, from about 10 to about 350 mg, or from about 50 to about
200 mg. The specific amount of the second active agent will depend on the
specific agent used, the disorder being treated or managed, the severity
and stage of the central nervous system disorder, and the amount(s) of an
immunomodulatory compound and any optional additional active agents
concurrently administered to the patient.

[0214]In certain embodiments, the prophylactic or therapeutic agents of
the invention are cyclically administered to a patient. Cycling therapy
involves the administration of a first agent for a period of time,
followed by the administration of the agent and/or the second agent for a
period of time and repeating this sequential administration. Cycling
therapy can reduce the development of resistance to one or more of the
therapies, avoid or reduce the side effects of one of the therapies,
and/or improves the efficacy of the treatment.

[0215]In a preferred embodiment, prophylactic or therapeutic agents are
administered in a cycle of about 24 weeks, about once or twice every day.
One cycle can comprise the administration of a therapeutic or
prophylactic agent and at least one (1) or three (3) weeks of rest. The
number of cycles administered is from about 1 to about 12 cycles, more
typically from about 2 to about 10 cycles, and more typically from about
2 to about 8 cycles.

[0216]4.4 Pharmaceutical Compositions and Single Unit Dosage Forms

[0217]Pharmaceutical compositions can be used in the preparation of
individual, single unit dosage forms. Pharmaceutical compositions and
dosage forms of the invention comprise an immunomodulatory compound of
the invention, or a pharmaceutically acceptable salt, solvate, hydrate,
stereoisomer, clathrate, or prodrug thereof. Pharmaceutical compositions
and dosage forms of the invention can further comprise one or more
excipients.

[0218]Pharmaceutical compositions and dosage forms of the invention can
also comprise one or more additional active ingredients. Consequently,
pharmaceutical compositions and dosage forms of the invention comprise
the active ingredients disclosed herein (e.g., an immunomodulatory
compound, or a pharmaceutically acceptable salt, solvate, hydrate,
stereoisomer, clathrate, or prodrug thereof, and a second active
ingredient). Examples of optional additional active ingredients are
disclosed herein (see, e.g., section 4.2).

[0220]The composition, shape, and type of dosage forms of the invention
will typically vary depending on their use. For example, a dosage form
used in the acute treatment of a disease may contain larger amounts of
one or more of the active ingredients it comprises than a dosage form
used in the chronic treatment of the same disease. Similarly, a
parenteral dosage form may contain smaller amounts of one or more of the
active ingredients it comprises than an oral dosage form used to treat
the same disease. These and other ways in which specific dosage forms
encompassed by this invention will vary from one another will be readily
apparent to those skilled in the art. See, e.g., Remington's
Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa.
(1990).

[0221]Typical pharmaceutical compositions and dosage forms comprise one or
more excipients. Suitable excipients are well known to those skilled in
the art of pharmacy, and non-limiting examples of suitable excipients are
provided herein. Whether a particular excipient is suitable for
incorporation into a pharmaceutical composition or dosage form depends on
a variety of factors well known in the art including, but not limited to,
the way in which the dosage form will be administered to a patient. For
example, oral dosage forms such as tablets may contain excipients not
suited for use in parenteral dosage forms. The suitability of a
particular excipient may also depend on the specific active ingredients
in the dosage form. For example, the decomposition of some active
ingredients may be accelerated by some excipients such as lactose, or
when exposed to water. Active ingredients that comprise primary or
secondary amines are particularly susceptible to such accelerated
decomposition. Consequently, this invention encompasses pharmaceutical
compositions and dosage forms that contain little, if any, lactose other
mono- or di-saccharides. As used herein, the term "lactose-free" means
that the amount of lactose present, if any, is insufficient to
substantially increase the degradation rate of an active ingredient.

[0222]Lactose-free compositions of the invention can comprise excipients
that are well known in the art and are listed, for example, in the U.S.
Pharmacopeia (USP) 25-NF20 (2002). In general, lactose-free compositions
comprise active ingredients, a binder/filler, and a lubricant in
pharmaceutically compatible and pharmaceutically acceptable amounts.
Preferred lactose-free dosage forms comprise active ingredients,
microcrystalline cellulose, pre-gelatinized starch, and magnesium
stearate.

[0223]This invention further encompasses anhydrous pharmaceutical
compositions and dosage forms comprising active ingredients, since water
can facilitate the degradation of some compounds. For example, the
addition of water (e.g., 5%) is widely accepted in the pharmaceutical
arts as a means of simulating long-term storage in order to determine
characteristics such as shelf-life or the stability of formulations over
time. See, e.g., Jens T. Carstensen, Drug Stability: Principles &
Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect,
water and heat accelerate the decomposition of some compounds. Thus, the
effect of water on a formulation can be of great significance since
moisture and/or humidity are commonly encountered during manufacture,
handling, packaging, storage, shipment, and use of formulations.

[0224]Anhydrous pharmaceutical compositions and dosage forms of the
invention can be prepared using anhydrous or low moisture containing
ingredients and low moisture or low humidity conditions. Pharmaceutical
compositions and dosage forms that comprise lactose and at least one
active ingredient that comprises a primary or secondary amine are
preferably anhydrous if substantial contact with moisture and/or humidity
during manufacturing, packaging, and/or storage is expected.

[0225]An anhydrous pharmaceutical composition should be prepared and
stored such that its anhydrous nature is maintained. Accordingly,
anhydrous compositions are preferably packaged using materials known to
prevent exposure to water such that they can be included in suitable
formulary kits. Examples of suitable packaging include, but are not
limited to, hermetically sealed foils, plastics, unit dose containers
(e.g., vials), blister packs, and strip packs.

[0226]The invention further encompasses pharmaceutical compositions and
dosage forms that comprise one or more compounds that reduce the rate by
which an active ingredient will decompose. Such compounds, which are
referred to herein as "stabilizers," include, but are not limited to,
antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0227]Like the amounts and types of excipients, the amounts and specific
types of active ingredients in a dosage form may differ depending on
factors such as, but not limited to, the route by which it is to be
administered to patients. However, typical dosage forms of the invention
comprise an immunomodulatory compound of the invention, or a
pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,
clathrate, or prodrug thereof in an amount of from about 1 to about 1,200
mg. Typical dosage forms comprise an immunomodulatory compound, or a
pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,
clathrate, or prodrug thereof in an amount of about 1, 2, 5, 10, 25, 50,
100, 200, 400, 800, 1,200, 2,500, 5,000 or 10,000 mg. In a particular
embodiment, a preferred dosage form comprises an immunomodulatory
compound in an amount of about 400, 800 or 1,200 mg. Typical dosage forms
comprise the second active ingredient in an amount of 1 to about 1000 mg,
from about 5 to about 500 mg, from about 10 to about 350 mg, or from
about 50 to about 200 mg. Of course, the specific amount of the second
active ingredient will depend on the specific agent used, the disorder
being treated or managed, and the amount(s) of an immunomodulatory
compound and any optional additional active agents concurrently
administered to the patient.

[0228]4.4.1 Oral Dosage Forms

[0229]Pharmaceutical compositions of the invention that are suitable for
oral administration can be presented as discrete dosage forms, such as,
but are not limited to, tablets (e.g., chewable tablets), caplets,
capsules, and liquids (e.g., flavored syrups). Such dosage forms contain
predetermined amounts of active ingredients, and may be prepared by
methods of pharmacy well known to those skilled in the art. See
generally, Remington's Pharmaceutical Sciences, 18th ed., Mack
Publishing, Easton Pa. (1990).

[0230]Typical oral dosage forms of the invention are prepared by combining
the active ingredients in an intimate admixture with at least one
excipient according to conventional pharmaceutical compounding
techniques. Excipients can take a wide variety of forms depending on the
form of preparation desired for administration. For example, excipients
suitable for use in oral liquid or aerosol dosage forms include, but are
not limited to, water, glycols, oils, alcohols, flavoring agents,
preservatives, and coloring agents. Examples of excipients suitable for
use in solid oral dosage forms (e.g., powders, tablets, capsules, and
caplets) include, but are not limited to, starches, sugars,
micro-crystalline cellulose, diluents, granulating agents, lubricants,
binders, and disintegrating agents.

[0231]Because of their ease of administration, tablets and capsules
represent the most advantageous oral dosage unit forms, in which case
solid excipients are employed. If desired, tablets can be coated by
standard aqueous or nonaqueous techniques. Such dosage forms can be
prepared by any of the methods of pharmacy. In general, pharmaceutical
compositions and dosage forms are prepared by uniformly and intimately
admixing the active ingredients with liquid carriers, finely divided
solid carriers, or both, and then shaping the product into the desired
presentation if necessary.

[0232]For example, a tablet can be prepared by compression or molding.
Compressed tablets can be prepared by compressing in a suitable machine
the active ingredients in a free-flowing form such as powder or granules,
optionally mixed with an excipient. Molded tablets can be made by molding
in a suitable machine a mixture of the powdered compound moistened with
an inert liquid diluent.

[0234]Suitable forms of microcrystalline cellulose include, but are not
limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL
RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose
Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. An
specific binder is a mixture of microcrystalline cellulose and sodium
carboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or low
moisture excipients or additives include AVICEL-PH-103® and Starch
1500 LM.

[0235]Examples of fillers suitable for use in the pharmaceutical
compositions and dosage forms disclosed herein include, but are not
limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and
mixtures thereof. The binder or filler in pharmaceutical compositions of
the invention is typically present in from about 50 to about 99 weight
percent of the pharmaceutical composition or dosage form.

[0236]Disintegrants are used in the compositions of the invention to
provide tablets that disintegrate when exposed to an aqueous environment.
Tablets that contain too much disintegrant may disintegrate in storage,
while those that contain too little may not disintegrate at a desired
rate or under the desired conditions. Thus, a sufficient amount of
disintegrant that is neither too much nor too little to detrimentally
alter the release of the active ingredients should be used to form solid
oral dosage forms of the invention. The amount of disintegrant used
varies based upon the type of formulation, and is readily discernible to
those of ordinary skill in the art. Typical pharmaceutical compositions
comprise from about 0.5 to about 15 weight percent of disintegrant,
preferably from about 1 to about 5 weight percent of disintegrant.

[0237]Disintegrants that can be used in pharmaceutical compositions and
dosage forms of the invention include, but are not limited to, agar-agar,
alginic acid, calcium carbonate, microcrystalline cellulose,
croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch
glycolate, potato or tapioca starch, other starches, pre-gelatinized
starch, other starches, clays, other aligns, other celluloses, gums, and
mixtures thereof.

[0241]Active ingredients of the invention can be administered by
controlled release means or by delivery devices that are well known to
those of ordinary skill in the art. Examples include, but are not limited
to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;
3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,
5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is
incorporated herein by reference. Such dosage forms can be used to
provide slow or controlled-release of one or more active ingredients
using, for example, hydropropylmethyl cellulose, other polymer matrices,
gels, permeable membranes, osmotic systems, multilayer coatings,
microparticles, liposomes, microspheres, or a combination thereof to
provide the desired release profile in varying proportions. Suitable
controlled-release formulations known to those of ordinary skill in the
art, including those described herein, can be readily selected for use
with the active ingredients of the invention. The invention thus
encompasses single unit dosage forms suitable for oral administration
such as, but not limited to, tablets, capsules, gelcaps, and caplets that
are adapted for controlled-release.

[0242]All controlled-release pharmaceutical products have a common goal of
improving drug therapy over that achieved by their non-controlled
counterparts. Ideally, the use of an optimally designed
controlled-release preparation in medical treatment is characterized by a
minimum of drug substance being employed to cure or control the condition
in a minimum amount of time. Advantages of controlled-release
formulations include extended activity of the drug, reduced dosage
frequency, and increased patient compliance. In addition,
controlled-release formulations can be used to affect the time of onset
of action or other characteristics, such as blood levels of the drug, and
can thus affect the occurrence of side (e.g., adverse) effects.

[0243]Most controlled-release formulations are designed to initially
release an amount of drug (active ingredient) that promptly produces the
desired therapeutic effect, and gradually and continually release of
other amounts of drug to maintain this level of therapeutic or
prophylactic effect over an extended period of time. In order to maintain
this constant level of drug in the body, the drug must be released from
the dosage form at a rate that will replace the amount of drug being
metabolized and excreted from the body. Controlled-release of an active
ingredient can be stimulated by various conditions including, but not
limited to, pH, temperature, enzymes, water, or other physiological
conditions or compounds.

[0244]4.4.3 Parenteral Dosage Forms

[0245]Parenteral dosage forms can be administered to patients by various
routes including, but not limited to, subcutaneous, intravenous
(including bolus injection), intramuscular, and intraarterial. Because
their administration typically bypasses patients' natural defenses
against contaminants, parenteral dosage forms are preferably sterile or
capable of being sterilized prior to administration to a patient.
Examples of parenteral dosage forms include, but are not limited to,
solutions ready for injection, dry products ready to be dissolved or
suspended in a pharmaceutically acceptable vehicle for injection,
suspensions ready for injection, and emulsions.

[0246]Suitable vehicles that can be used to provide parenteral dosage
forms of the invention are well known to those skilled in the art.
Examples include, but are not limited to: Water for Injection USP;
aqueous vehicles such as, but not limited to, Sodium Chloride Injection,
Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride
Injection, and Lactated Ringer's Injection; water-miscible vehicles such
as, but not limited to, ethyl alcohol, polyethylene glycol, and
polypropylene glycol; and non-aqueous vehicles such as, but not limited
to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,
isopropyl myristate, and benzyl benzoate.

[0247]Compounds that increase the solubility of one or more of the active
ingredients disclosed herein can also be incorporated into the parenteral
dosage forms of the invention. For example, one might use cyclodextrin
and its derivatives to increase the solubility of an immunomodulatory
compound.

[0248]4.4.4 Topical and Mucosal Dosage Forms

[0249]Topical and mucosal dosage forms of the invention include, but are
not limited to, sprays, aerosols, solutions, emulsions, suspensions, or
other forms known to one of skill in the art. See, e.g., Remington's
Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing,
Easton Pa. (1980 & 1990); and Introduction to Pharmaceutical Dosage
Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable
for treating mucosal tissues within the oral cavity can be formulated as
mouthwashes or as oral gels.

[0250]Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide topical and mucosal dosage forms
encompassed by this invention are well known to those skilled in the
pharmaceutical arts, and depend on the particular tissue to which a given
pharmaceutical composition or dosage form will be applied. With that fact
in mind, typical excipients include, but are not limited to, water,
acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol,
isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures
thereof to form solutions, emulsions or gels, which are non-toxic and
pharmaceutically acceptable. Moisturizers or humectants can also be added
to pharmaceutical compositions and dosage forms if desired. Examples of
such additional ingredients are well known in the art. See, e.g.,
Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack
Publishing, Easton Pa. (1980 & 1990).

[0251]The pH of a pharmaceutical composition or dosage form may also be
adjusted to improve delivery of one or more active ingredients.
Similarly, the polarity of a solvent carrier, its ionic strength, or
tonicity can be adjusted to improve delivery. Compounds such as stearates
can also be added to pharmaceutical compositions or dosage forms to
advantageously alter the hydrophilicity or lipophilicity of one or more
active ingredients so as to improve delivery. In this regard, stearates
can serve as a lipid vehicle for the formulation, as an emulsifying agent
or surfactant, and as a delivery-enhancing or penetration-enhancing
agent. Different salts, hydrates or solvates of the active ingredients
can be used to further adjust the properties of the resulting
composition.

[0252]4.4.5 Kits

[0253]Typically, active ingredients of the invention are preferably not
administered to a patient at the same time or by the same route of
administration. This invention therefore encompasses kits which, when
used by the medical practitioner, can simplify the administration of
appropriate amounts of active ingredients to a patient.

[0254]A typical kit of the invention comprises a dosage form of an
immunomodulatory compound of the invention, or a pharmaceutically
acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug
thereof. Kits encompassed by this invention can further comprise
additional active ingredients. Examples of the additional active
ingredients include, but are not limited to, those disclosed herein (see,
e.g., section 4.2).

[0255]Kits of the invention can further comprise devices that are used to
administer the active ingredients. Examples of such devices include, but
are not limited to, syringes, drip bags, patches, and inhalers.

[0256]Kits of the invention can further comprise pharmaceutically
acceptable vehicles that can be used to administer one or more active
ingredients. For example, if an active ingredient is provided in a solid
form that must be reconstituted for parenteral administration, the kit
can comprise a sealed container of a suitable vehicle in which the active
ingredient can be dissolved to form a particulate-free sterile solution
that is suitable for parenteral administration. Examples of
pharmaceutically acceptable vehicles include, but are not limited to:
Water for Injection USP; aqueous vehicles such as, but not limited to,
Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,
Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;
water-miscible vehicles such as, but not limited to, ethyl alcohol,
polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles
such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame
oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0257]4.4.6 Cycling Therapy in Central Nervous System Disorders

[0258]In a specific embodiment, an immunomodulatory compound is cyclically
administered to patients with central nervous system disorders. Cycling
therapy involves the administration of a first agent for a period of
time, followed by the administration of the agent and/or the second agent
for a period of time and repeating this sequential administration.
Cycling therapy can reduce the development of resistance to one or more
of the therapies, avoid or reduce the side effects of one of the
therapies, and/or improves the efficacy of the treatment.

[0259]In a specific embodiment, prophylactic or therapeutic agents in an
amount of about 400, 800 or 1200 mg are administered in a cycle of about
24 weeks, about once or twice every day. One cycle can comprise the
administration of a therapeutic on prophylactic agent and at least one
(1), two (2), or three (3) weeks of rest. The number of cycles
administered is from about 1 to about 12 cycles, more typically from
about 2 to about 10 cycles, and more typically from about 2 to about 8
cycles.

5. EXAMPLES

[0260]The following studies are intended to further illustrate the
invention without limiting its scope.

[0261]5.1 Studies in Amyotrophic Lateral Sclerosis

[0262]The effects of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione in a
model of Amyotrophic Lateral Sclerosis are investigated in mice.
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is
administered to Male Transgenic mice overexpressing the human mutated
form (G93A) of Cu,Zn-superoxide dismutase (mSOD1) (Science, 302, 113-117,
2003) once or twice daily for 14 days. Anti-ALS activity of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is
assessed by measuring rescue of motoneurons or prolongation of survival
in comparison to the reference compound, riluzole.

[0263]5.2 Studies in Parkinson Disease

[0264]The effects of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione in a
model of Parkinson disease are investigated in mice. Male C57/BL6 mice
are injected once daily for 7 days with MPTP (30 mg/kg, i.p.).
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is
administered once or twice daily for 14 days. On day 28, striata are
removed, homogenized in perchloric acid, and centrifuged. The supernatant
is removed and analyzed for dopamine and other monoamines such as
serotonin by reverse-phase HPLC and electrochemical detection.
Anti-Parkinson activity of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is
assessed in comparison to the reference compound, selegiline.

[0268]On day 1 in a cycle of 24 weeks, blood product transfusion is
administered to patients with ALS. On day 10, the administration of 800
mg/d of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
is started. On day 30, blood product transfusion is administered. On day
34, the administration of 800 mg/d of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is
stopped. On day 59, the administration of 400 mg/d of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is
begun.

[0269]Embodiments of the invention described herein are only a sampling of
the scope of the invention. The full scope of the invention is better
understood with reference to the attached claims.